Pancreatic adenocarcinoma is the fifth leading cause of cancer deaths in the United States, with a five-year survival rate of less than five percent. Nuclear Factor kappa B (NFκB) is a dimeric transcription factor that has been implicated in suppression of apoptosis, angiogenesis, and metastasis.
Acanthoic acid is a pimaradiene diterpene isolated from the Korean medicinal plant, Acanthopanax koreanum Nakai (Araliaceae). The root and stem barks of Acanthopanax koreanum have been used in traditional medicine as a tonic and sedative as well as in the treatment of rheumatism and diabetes in Korea. Acanthopanax koreanum Nakai (Araliaceae), which is found indigenously in Cheju Island, The Republic of Korea, has also been used traditionally as a remedy for, for example, neuralgia, paralysis, and lumbago. Various useful components, including acanthoic acid, a compound having the chemical structure of Formula (I), have been isolated from the root bark of this tree. Furthermore, certain analogs of the compound of Formula (I), for example, wherein the COOH group is replaced by a methanolic group, by a methyl-acetyl ether, by a methyl group, and by a methyl-ester have each also been isolated from the root bark of Acanthopanax koreanum Nakai (Araliaceae). See Kim, Y. H. and Chung, B. S., J. Nat. Pro., 51, 1080-83 (1988). (The proper chemical names of these analogs are provided in this reference.) This reference and all the other patents and printed publication cited herein are, in their entirety, incorporated by reference herein.

The compound of Formula (I), also known as acanthoic acid, has been reported to have certain pharmacological effects, including, for example, analgesic and anti-inflammatory activity. The compound of Formula (I) also exhibits very low toxicity; 1000 mg/kg is the minimum lethal dose (MLD) when administered orally or I.V. to a rat (See Lee, Y. S., “Pharmacological Study for (−)-Pimara-9(11), 15-Diene-19-oic Acid, A Component of Acanthopanax koreanum Nakai,” Doctorate Thesis, Dept. of Pharmacy, Seoul National University, Korea (1990)). The compound of Formula (I) and/or its naturally-occurring analogs, may exhibit these known pharmacological effects by inhibiting leukocyte migration and prostaglandin E2(PGE2) synthesis, and is a suspected effector of both Interleukin-1 (IL-1) and Tumor Necrosis Factor-α (TNF-α) production. Additionally, a process for the preparation of acanthoic acid, and use of the acanthoic acid for treatment of immune disease is described in International Patent Publication WO 95/34300 (Dec. 21, 1995).
Also, the compound of Formula (IA), kauranoic acid, and the corresponding methyl-ester analog of the compound of Formula (IA), as well as methanolic reduction analogs of the compound of Formula (IA) have been isolated from the root bark of Acanthopanax koreanum Nakai (Araliaceae). See Kim, Y. H. and Chung, B. S., J. Nat. Pro., 51, 1080 (1988). (The proper chemical name of kauranoic acid, (−)-kaur-16-en-19-oic acid, and of the known analogs of kauranoic acid are provided in this reference.)

Tumor Necrosis Factor-α (herein “TNF-α” or “TNF”) and/or Interleukin-1 (herein “IL-1”) are involved in various biochemical pathways and, thus modulators of TNF-α and/or IL-1 activity or production and other molecules regulated by TNF-α or Il-1, especially novel modulators of TNF-α and/or IL-1 activity or novel compounds that influence the production of either IL-1 or TNF-α, or both, are highly desired. Such compounds and classes of compounds would be valuable in maintaining the human immune system and in treating diseases such as for example, tuberculous pleurisy, rheumatoid pleurisy, and diseases not conventionally considered to be immune disorders, such as cancer, cardiovascular disease, skin redness, viral infection, diabetes, and transplant rejection.
Although numerous approaches to regulate the production of TNF-α and the interleukins are known, novel approaches, compounds, and pharmaceutical formulations to regulate the production of TNF-α and interleukins are highly desirable and have been long sought by those of skill in the art.